Salicylazosulfapyridine (SASP) has been known to be effective in the treatment of ulcerative colitis and has been used clinically for that purpose for over 30 years. When the drug is orally ingested, most reaches the colon intact where it suffers reductive azo-cleavage as a result of action of colonic bacteria to give sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA). SP is abosrbed, distributed throughout the body, and excreted in urine as glucuronide conjugates. Approximately 30% of the 5-ASA is absorbed from the colon, acetylated and excreted in the urine and the remainder is excreted in the feces.
It was determined that the therapeutic mechanism of SASP was primarily a function of the anti-inflammatory 5-ASA and most of the deleterious side effects were associated with SP. Accordingly, 5-ASA has been formulated in a form bound to a suitable polymer for site specific release of 5-ASA in the colon while avoiding the presence of the toxic SP portion of SASP. This is described in Parkinson, et al. U.S. Pat. No. 4,190,716.
5-ASA is unique in that before the present invention, it was the only non-steroidal anti-inflammatory agent known to be useful in the treatment of ulcerative colitis. Other salicylates such as aspirin (acetylsalicylic acid) and other anti-inflammatories such as indomethacin (which is a more potent anti-inflammatory agent) are not effective in the treatment of ulcerative colitis.
4-Aminosalicylic acid (4-ASA) is a well known pharmaceutical agent which has been used for many years in the treatment of tuberculosis. 4-ASA has a bacteriostatic effect on the organism Mycobacterium tuberculosis and inhibits the development of bacterial resistance to streptomycin and isoniazid. 4-ASA has invariably been administered as part of a multi-drug regimen including one or both of these drugs.
Even though 4-ASA and 5-ASA are position isomers, they are well recognized to be quite distinct chemically. The salicylic acid backbone is a carboxy-substituted phenol and it is well known that the phenolic hydroxy group or alkoxide ion is a very powerful activator of the benzene ring directing ortho- and para- in electrophylic aromatic substitution. As a result, meta-substituted salicylic acids on one hand, and para- or ortho-substituted salicylic acids on the other hand, are prepared via different processes and undergo different reactions. For example, the meta-substituted 5-ASA is produced by the reduction of a nitro compound by zinc dust and hydrochloric acid or by electrolytic reduction. The para-substituted 4-ASA is prepared by heating 3-aminophenol with ammonium carbonate or potassium bicarbonate under pressure or from the corresponding sodium salt (U.S. Pat. No. 2,844,625). The meta-substituted 5-ASA is very unstable and is known to quickly break down to a dark purple presumed quinone containing tar. The para-substituted 4-ASA also breaks down into a brownish or purplish material but at a much slower rate. Four-ASA, in the presence of moisture readily decarboxylates, whereas 5-ASA does not. Salts of 4-ASA resist decarboxylation. Further, even though 4-ASA has been used for the treatment of millions of tuberculosis patients, there has been no recognition of the anti-inflammatory activity of this compound. Similarly, 5-ASA is not known to be anti-tubercular. Still futher, 4-ASA cannot, because of the steric and activity differences from 5-ASA, be bound to the same polymers as 5-ASA or to other polymers using methods applicable to 5-ASA.
In view of the well recognized distinction chemically between 4-ASA and 5-ASA, it was quite surprising to discover that not only did 4-ASA have anti-inflammatory activity but also it was roughly 50% more potent than 5-ASA. Since the 4-amino compound is more potent and as a salt is also more resistant to degradation, doses which are smaller in absolute amounts can be administered thereby decreasing the magnitude and/or occurence of adverse side effects.
It is accordingly the object of this invention to provide a new anti-inflammatory agent which is useful, interalia, in the treatment of ulcerative colitis and more broadly in inflammatory bowel disease. This and other objects of the invention will become apparent to those skilled in the art from the following detailed disclosure.